DESCRIPTION Alterations in skeletal muscle sarcoplasmic reticulum (SR) calcium (Ca/2+) release have been identified in a number of conditions associated with muscle dysfunction including eccentric muscle injury, malignant hyperthermia, congestive heart failure, and activity induced fatigue (see sec. 29b). Based on the study of whole cell Ca/2+ transients and isolated SR heart failure, and activity induced fatigue (see sec.29b). Based on the study of whole cell Ca/2+ transients and isolated SR proteins, the mechanisms by which the SR Ca/2+ channel regulates release have been hypothesized. Recently, however, techniques utilizing laser scanning confocal microscopy and the Ca/2+ indicator Fluo-3 have allowed the imaging of discrete localized Ca/2+ release events (Ca/2+ sparks) in functionally intact skeletal muscle. Examination of these events in response to either voltage or ligand stimulation is providing insight into the control of SR Ca/2+ release at the cellular level. The main objective of this proposal is to examine the local control of SR Ca/2+ release in functionally intact skeletal muscle fibers. Specifically, I intend to examine the effect of ligand modulation of skeletal muscle Ca/2+ spark properties to gain insight into the normal functioning of SR Ca/2+ release in-vivo. Additionally, measurements will be made on muscle fibers which have an impaired SR Ca/2+ release mechanism to investigate the contribution of Ca/2+ sparks to the decline in global SR function.